Background: Checkpoint blockade immunotherapy has become an essential therapeutic armamentarium for treating patients with advanced lung cancer. However, it is an unmet clinical need to improve the therapeutic outcome, given the fact that only a subset of patients are benefitting from immunotherapy. As we understand more about the mechanisms of response and resistance, numerous clinical trials are now underway to test combination therapy to improve the responses. EZH2, an enzymatic component of Polycomb Repressive Complex (PRC) 2 emerged as a viable target for patients with lung cancer based on the studies showing poor prognosis with its overexpression and improved tumor control in the mouse models in combination therapy, particularly with checkpoint blockade immunotherapy. In addition, a first oral EZH2 inhibitor, tazemetostat, was approved by FDA in early 2020 for patients with advanced epithelioid sarcoma. Therefore, we propose to test the combination treatment with tazemetostat and pembrolizumab for Veteran patients with advanced non-small cell lung cancer (NSCLC). Hypothesis: EZH2 inhibitor, tazemetostat, is able to re-sensitize cancer cells responding to checkpoint blockade immunotherapy. Objectives: Primary objectives: Safety and efficacy of the tazemtostat and pembrolizumab combination treatment for patients with advanced NSCLC who progressed from the front or 2nd line of therapy measured by Objective Response Rate assessed by RECIST v1.1. Secondary objectives: Disease control rate, progression free survival, one-year survival rate and duration of response. Specific aims: Aim 1. Perform an open label single arm phase Ib/II study of safety and efficacy of the EZH2 inhibitor, tazemetostat, and PD-1 blockade, pembrolizumab, for treatment of patients with advanced NSCLC. Aim 2. Perform exploratory analyses to identify correlative clinical or molecular markers (biomarkers) of response and resistance to this combination therapy. Study design: Aim 1. Utilize 3+3 standard dose escalation strategy to determine recommended phase II dose with 3 dose levels, 400, 600 and 800 mg twice daily of tazemetostat combined with flat dose, 200 mg of intravenous pembrolizumab. For phase II, we are aiming to enroll a total of 54 patients using Simon Optimum Two Stage design to test the efficacy. Aim 2. Biomarker and correlative studies. Primary biomarkers to be tested, H3K27me3 and PD-L1 using tumor biopsies. Tumor mutational burden, neoantigen and cell free DNA (ctDNA) dynamics will be tested using tumor biopsies and serial blood draw along with immune monitoring (immunophenotype via flow/CyTOF, NanoString and multiplex immunofluorescence). Relevant to Military health: Improving treatment of many types of advanced cancers is critically important to the health of Veterans. Many Veterans suffer from significant morbidity when they are diagnosed with cancer that limits their therapeutic options. Immunotherapy is generally well tolerated and has a significant poten...